Intracellular receptors (IR) form a class of structurally related gene regulators known as "ligand dependent transcription factors" (R. M. Evans, Science 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound that inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus that can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann et al, Ann. N.Y. Acad. Sci. 261, 248, 1995), in combination with a PR agonist (Kekkonen et al, Fertility and Sterility 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy et al, J. Clin. Endo. Metab. 76, 513, 1993) and endometriosis (Kettel et al, Fertility and Sterility 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna et al, Ann. N.Y. Acad. Sci. 761, 224, 1995).
Jones et al (U.S. Pat. No. 5,688,810) described the PR antagonist dihydroquinoline A. ##STR2##
Jones et al described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. ##STR3##
Jones et al described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. ##STR4##
Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem. 41, 291, 1998). ##STR5##
Zhi et al described the ether G as a PR antagonist (J. Med. Chem. 41, 291, 1998). ##STR6##
Combs et al disclosed the amide H as a ligand for the PR (J. Med. Chem. 38, 4880, 1995). ##STR7##
Perlman et al described the vitamin D analog I as a PR ligand (Tetrahedron. Lett. 35, 2295, 1994). ##STR8##
Hamann et al described the PR antagonist J (Ann. N.Y. Acad. Sci. 761, 383, 1995). ##STR9##
Chen et al described the PR antagonist K (Chen et al, POI-37, 16.sup.th Int. Cong. Het. Chem., Montana, 1997). ##STR10##
Kurihari et al described the PR ligand L (J. Antibiotics 50, 360, 1997). ##STR11##
There are several examples of 2,1-benzisothiazoline 2,2-dioxides (`sultams`) in the chemical and patent literature which contain no reference to progesterone activity, and do not carry the correct substitution pattern for PR modulator activity.
Chiarino et al described the preparation of the parent 2,1-benzisothiazoline 2,2-dioxide, i.e., M (and derivatives, e.g., N), that was used in the present invention (J. Heterocycl. Chem. 23(6), 1645-9, 1986). ##STR12##
Skorcz et al described a series of 5-(2-morpholinyl)-2,1-benzisothiazolines, e.g., O, which are useful as central nervous depressants (U.S. Pat. No. 3,635,964). ##STR13##
Kamireddy et al disclosed a series of cyclic sulfonamides, e.g., P and Q, useful for controlling undesired vegetation (WO 95/33746). ##STR14##